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    • There are essentially two screening strategies

    2023-03-22

    There are essentially two screening strategies to minimize the number of newborns recalled for additional testing without missing cases for most screening disorders. For hyperargininemia, one strategy uses Arg alone as the indicator of possible disease and the other uses Arg in combination with a ratio (or ratios) of related amino acids. In the first method (Arg alone), in order to eliminate missing cases, relatively large numbers of patients must be recalled to further assess other laboratory and clinical information before confirming the presence of disease (Table 3). Reduced recall can be accomplished by raising the cutoff value thus increasing the possibility for missing cases. The second strategy reduces the numbers recalled through a filtering process. A lower Arg cutoff can be used to initially create a larger pool of potentially abnormal patients (thus lowering the chances of missing a case) whose numbers are then reduced by examining laboratory values for other analytes, assessed as various amino Lonafarnib mg ratios. The difficulty comes in determining which ratios are reliable discriminators of disease. For either of these screening strategies, large numbers of screens are required in order to estimate the sensitivity and specificity of the screening algorithm. Screening algorithms for NBS can be developed using multivariate pattern recognition software and metabolic profile scoring along with large datasets such as the international R4S [16]. Additionally, tools such as the R4S Tool Runner have been created to provide further assistance in assessing various ratios as their value as secondary discriminators for various diseases [8], [9]. While most U.S. NBS programs are aware of and participate in contributing to the R4S database, our state survey data indicated that its use in developing state NBS algorithms was minimal and only one state program reported routinely using Tool Runner as a NBS aid. In order to consider the possible effectiveness of the various hyperargininemia NBS protocols reported, we retrospectively compared various algorithms using California NBS data. In addition to the routine Arg/Orn ratio used in California and many other programs, the ratio of Arg/(Leu×Phe) is used in the New England Regional Program. Using these two ratios and an initial cutoff value for arginine of 50μM, all 9 known cases of arginase 1 deficiency detected in California over the 2005–2015 period (Table 1) would have been ascertained with no false screen positive cases reported. While the low frequency of arginase 1 deficiency in the population precludes absolute statements, we can state with certainty that the sensitivity of this screening protocol is very high and the specificity approaches 100%. Because cases of metabolic disorders missed by newborn screening are reportable in California, it is relatively certain that no unknown cases of the disorder are present in California newborns, although early misdiagnosis is always a possibility. Thus, despite its rarity, screening for arginase 1 deficiency is practical when these ratios are used. Moreover, when each case was examined using the R4S Tool Runner, all were ascertained with a calculated false positive rate of <0.005%. Determining status and value of newborn screening for hyperargininemia is complicated by a scarcity of published case detection and treatment data. Available case detection data do not support specific ethnic or geographic predilections, although hyperargininemia appears to be higher in Japan, Portugal and among French-Canadians of pioneer origin. While NBS in the U.S. is still not universal, 38U.S. state programs currently report arginine results, and are therefore likely to observe hyperargininemia cases. While the apparent 1:1.2M minimum incidence observed through NBS to date is similar in magnitude to that of some of the other metabolic conditions currently included in NBS, continued data collection is needed to establish a more reliable incidence. The ACMGG ACT sheet for the follow-up of presumptive positive newborn screening results (i.e. elevated arginine) suggests obtaining a repeat arginine level along with a quantitative urinary orotic acid level [17]. While elevated orotic acid in the urine of hyperargininemia patients was reported by one of us, S.C., in 1981 [18] and subsequently found to be elevated in a number of infants with the disorder, we believe that this test has been insufficiently validated to be reliable for diagnosis. On the other hand, red blood cell arginase enzyme levels and mutation analysis of the exons of the arginase gene have been demonstrated to be reliable and together are the follow-up methods of choice [4]. Although the enzyme assay has been validated only in symptomatic patients, extrapolation to those who may be less severely affected seems appropriate. The normal levels in infants appear to be the same as in older children and adults, although this has not been studied extensively.